This invention relates to a process for obtaining new mixed copper amino acidate compounds from 1,10-phenanthrolines and their 4-7-dimethyl derivatives and the compounds obtained thereby to be used as anticancerigenic agents preferably in a therapeutic treatment of liquid and solid cancerigenic tumors such as leukemia. The compounds obtained are of the .sup.+ NO.sub.3.sup.- type in which the (N--N) ligand corresponds to 1,10-phenanthroline or 4,7-dimethyl-1,10 phenanthroline and the (N--O) ligand corresponds to one of the amino acidates such as tyrosine-alaninate, treoninate, triptophanate, valinate, isoleucinate, cysteinate, diglycinate, phenylalaninate, glycinate, histidinate, serinate, tyrosinate, aspartate, and alaninate.
The process is characterized by the following steps: making an aqueous solution of an aliphatic alcohol and the phenanthroline and reacting the solution with a copper complex, preferably Cu(NO.sub.3).sub.2.5H.sub.2 O, at room temperature. Immediately after making the product, reacting it with an amino acidate in an aqueous solution while adjusting it to a slightly alkaline pH.
A type of drug for which a correlation between biological activity and structure has been found is the metal chelating agent such as iron, ruthenium, cobalt, manganese, zinc and copper (Dwyer, F. P. et al. Nature, 179 (1956), 425-426). Chelating agents can be designed to inactivate bacteria, viruses and fungi by capturing the metallic ions necessary for the metabolism of these microorganisms. They can also be supplied with metallic ions that prove toxic to them.
Studies related to the composition of physiological fluids have shown that the metallic ions present in these systems are largely found in the form of mixed complexes. Here the term mixed complex must be understood to mean all those coordination complexes with two or three chelate type ligands that are different one from the other, excluding the solvent of the chelate ligand category.
Sigel and colleagues (Sigel. H. et al., JACS 99:13 (1976), 4489-4496) have shown that in many cases the enzymatic action depends on an elementary process in which an enzyme-substrate complex is generated that presents characteristics analogous to those of a mixed complex.
Certain metallic chelates supplied in small concentrations are active against some bacteria, fungi, viruses and some tumorous cells.
It is well known, for instance, that Staphylococcous pyrogenes, which has been detected in infected wounds and has proved to be highly resistant to the action of many standard antibiotics, perishes in the presence of the iron and ruthenium (tetramethyl- 1,10phenanthroline)(acetylacetone).sup.+ complexes. The biological activity of these saturated chelate complexes is principally due to the stereochemistry of the complex as a whole, the ionic nature of the coordination sphere, the nature of the coordination center, the lyophilicity of the ligands, the redox potentials of the complexes, and the thermodynamic stability and kinetics of the metallic chelates.
Voloir and colleagues have studied the catalytic activity of the Co(II) and Cu(II) complexes with orthophenanthrolines in the oxidation processes of the NADH, Q.sub.4 H.sub.2 (quinone), Q.sub.9 H.sub.2 (ubiquinone) and cytochrome C substrates.
The [Cu(2,9-dimethyl-1.10-phenanthroline).sub.2 ]C1.sub.2 complex is an effective inhibitor of the growth of the plasmodium Micoplasmacillisepticum, a very dangerous pathogenic microorganism that induces pulmonary diseases in man. D. R. Williams has calculated the distribution percentages of the Cu(II). Fe(II). Mn(II) and Zn(II) ions with low weight ligands, the predominant molecules in human blood plasma: Cu(hys)(cys); (Cu(hys).sub.2 ; and Cu (hys)(cysh).sup.+ are among the most abundant complexes.
Mention is made in the literature of studies on the absorption of the Mn(gly).sub.2 and Mn(L-ala).sub.2 chelate complexes through the intestinal wall in dogs.
Kwik and colleagues have reported the synthesis of mixed complexes with the general formula [Cu(phenanthroline)(aminoacidate)X].sub.n H.sub.2 O, [Cu(bipyridine)(aminoacidate)X].sub.n H.sub.2 O), where x is C1 or 1/2 SO.sub.4 and the amino acidate is glycinate, alaninate, valinate, tyrosinate, serinate, aspartate or glutamate.
Where the general synthesis method consists of preparing an aqueous solution with 5 mmol of CuSO.sub.4 5H.sub.2 O in 20 ml of distilled water which is slowly added to an ethanol solution, a solution blue in color is immediately formed. The mixture is magnetically shaken and at the same time a solution of 10 ml of HCl 0.1 M that contains one of the amino acidates is added, immediately followed by a solution of ammonium hydroxide 1 M until the solution becomes clear. The mixture that has been thus prepared is heated and shaken for 30 minutes; the heating process is continued until the volume is reduced by half. The product obtained is cooled in ice until a solid is formed, it is filtered, washed in small pieces in cold water and then in ethanol and is finally vacuum dried.
The applicant has developed a process to obtain new chelates by means of the synthesis and characterization of mixed chelate complexes of ions Mn(II), Fe(II), Ni(II), Co(II. III), Cu(II) Zn(II) and Ru(II) with ligands of the N--N(phenanthrolines and bipyridines and methyl substituted derivatives), O--O(acethylacetonate and salycilaldehydate ions) and N--O(amino acidate ions) type. These mixed chelate complexes have some type of potential biological activity.
With the ion Cu(II) and phenanthroline and their 4,7 dimethyl derivatives, complexes of the [CU(N--N)(N--O)].sup.+ NO.sub.3.sup.- type have been isolated.